Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites

Capecitabine (Xeloda) is a rationally designed oral, tumor-selective fluoro pyrimidine carbamate aimed at preferential conversion to 5-fluorouracil (5- FU) within the tumor. Because capecitabine is extensively metabolized by th e liver, it is important to establish whether liver dysfunction altered the pharmacokinetics of capecitabine and its metabolites. This was investigate d in 14 cancer patients with normal liver function and in 13 with mild to m oderate disturbance of liver biochemistry due to liver metastases. They rec eived a single oral dose of capecitabine (1255 mg capecitabine/m(2)) with s erial blood and urine samples collected up to 72 h after administration. Co ncentrations of capecitabine and its metabolites were determined in plasma by high-performance liquid chromatography or liquid chromatography coupled to mass spectrometry and in urine by F-19-nuclear magnetic resonance spectr oscopy. Although plasma concentrations of capecitabine, 5'-deoxy-5-fluorour idine, 5-FU, dihydro-5-FU, and alpha-fluoro-beta-alanine were, in general, higher in patients with liver dysfunction, the opposite was found for 5'-de oxy-5-fluorocytidine. These effects were not clinically significant. Total urinary recovery of capecitabine and its metabolites was 71% of the adminis tered dose in patients with normal hepatic function and 77% in patients wit h hepatic impairment, The absolute bioavailability of 5'-deoxy-5-fluorourid ine was estimated as 42% in patients with normal hepatic function and 62% i n patients with impaired hepatic function. In summary, mild to moderate hep atic dysfunction had no clinically significant influence on the pharmacokin etic parameters of capecitabine and its metabolites. Although caution shoul d be exercised when capecitabine is administered to patients with mildly to moderately impaired hepatic function, there is no need for, a priori, adju stment of the dose.